Background

Adenovirus, a DNA virus, was first isolated in the 1950s in adenoid tissue–derived cell cultures, hence the name. These primary cell cultures were often noted to spontaneously degenerate over time, and adenoviruses are now known to be a common cause of asymptomatic respiratory tract infection that produces in vitro cytolysis in these tissues.

A virus image from the International Committee on Taxonomy of Viruses, in The Big Picture Book of Viruses, available at http://www.virology.net/Big_Virology/BVDNAadeno.html.

An extremely hardy virus, adenovirus is ubiquitous in human and animal populations, survives long periods outside a host, and is endemic throughout the year. Possessing 52 serotypes, adenovirus is recognized as the etiologic agent of various diverse syndromes. It is transmitted via direct inoculation to the conjunctiva, a fecal-oral route, aerosolized droplets, or exposure to infected tissue or blood.

The virus is capable of infecting multiple organ systems; however, most infections are asymptomatic. Adenovirus is often cultured from the pharynx and stool of asymptomatic children, and most adults have measurable titers of anti-adenovirus antibodies, implying prior infection. Adenovirus is known to be oncogenic in rodents but not in humans.

Adenovirus has been associated with both sporadic and epidemic disease and, with regard to infections among military recruits, who were routinely immunized against types 4 and 7 from 1971 until the cessation of vaccine production in 1996. Adenovirus became a significant cause of economic cost and morbidity in this setting. A live oral vaccine against adenovirus types 4 and 7 was approved for use in this population by the US Food and Drug Administration (FDA) in 2011, and subsequent incidence of acute respiratory disease declined.

Of interest is the role of adenoviruses as vectors in vaccination and in gene therapy.
[1, 2, 3] Adenoviruses can infect various cells, both proliferating and quiescent, and thus hold the promise of targeting many different tissues and diseased cell lines.

The genome of adenovirus is well known and can be modified with relative ease to induce lysis or cytotoxicity of a specified cell line without affecting others.

The virus itself can be engineered to remove its replicative capacity by removing essential genes. Additionally, specific genes can be inserted into the virus that then can repair defective metabolic, enzymatic, or synthetic pathways in the host. Suicide gene systems that convert nontoxic systemically delivered prodrugs to active chemotherapeutic agents have been delivered via adenoviral vectors directly into cancer cells. However, the greatest challenge in viral gene therapy, as might be expected, is the immune response to the viral vector itself.

The complex mechanisms by which viral vectors may be incorporated into gene therapy and the rapid growth in this field put further discussion beyond the scope of this text.

Next:

Pathophysiology

Adenovirus is a double-stranded DNA virus that measures 70-90 nm and that has an icosahedral capsid.

The site of entry generally determines the site of infection; respiratory tract infection infections result from droplet inhalation, while gastrointestinal tract involvement results from fecal-oral transmission. Upon infection with adenovirus, one of three different interactions with the cells may occur.

The first is lytic infection, which occurs when an adenovirus enters human epithelial cells and continues through an entire replication cycle, which results in cytolysis, cytokine production, and induction of host inflammatory response.

The second is chronic or latent infection, the exact mechanism of which is unknown, which frequently involves asymptomatic infection of lymphoid tissue.

Lastly, oncogenic transformation has been observed in rats. During oncogenesis, the replication cycle is truncated, and adenoviral DNA is then integrated into the host cell’s DNA. Thereafter, adenovirus produces potent E1A proteins that immortalize primary rodent cells by altering cellular transcription, ultimately leading to deregulation of apoptosis and malignant transformation.

Previous

Next:

Epidemiology

Frequency

United States

Adenovirus is isolated most commonly in infants and children. An increased incidence of infection was found in military recruits until the introduction of an effective vaccine against serotype 4 (Ad4) and serotype 7 (Ad7) in 1971. The economy-driven cessation of vaccine production by its sole producer in 1996 resulted in re-emergence of outbreaks, with Ad4 predominating in 98% of cases. The reservoirs exist within the crowded training environment itself, and Ad4 has been detected on lockers, rifles, and bedding. Ad4 seropositivity of new recruits has been demonstrated to rise from 30% to almost 100%. Prolonged pharyngeal shedding and communal quarters contribute to outbreaks, with illness most commonly arising in weeks 3 to 5.

Lost productivity and interrupted military training prompted reinvestigation of vaccine production. Live oral adenovirus types 4 and 7 vaccine was approved by the FDA in 2011, significantly decreasing and the incidence of febrile respiratory illness. Notably, co-infection with non-vaccine strains (B1 and E) have developed following vaccination,
[4] and surveillance for emerging non-vaccine strains is still needed.

Mortality/Morbidity

Severe morbidity and mortality associated with adenovirus infections are rare in immunocompetent hosts. Uncommon complications that increase the risk of mortality include meningoencephalitis and pneumonitis.

Severe adenovirus infections have been reported in immunocompromised patients, such as transplant patients and those with inherited and acquired immunodeficiency states. Mortality rates associated with adenovirus infections among pediatric and adult transplant recipients have varied from 6%-70%.
[5]

Morbidity and deaths due to pronounced host inflammatory responses have occurred in past gene vector trials.

As with polio vaccines, live adenovirus vaccines in the 1950s became contaminated with simian virus 40 (SV40), with resulting concern that this virus caused various cancers. After subsequent long-term follow-up, some studies have found a moderate association between SV40 and human cancers as a transforming virus, while some other studies have reported no such findings.
[6, 7]

Race

No racial predilection has been described.

Sex

Adenovirus urinary tract infections are more common in males. The prevalence of other syndromes does not appear to be affected by the sex of the individual.

Age

Adenovirus infection typically affects children from infancy to school age, but children of any age may be affected, including neonates. Young adults in any setting of close quarters and stress may be affected, as in the case of military trainees.

Previous

Next:

Prognosis

The prognosis of adenovirus infection is generally good in immunocompetent hosts, but mortality rates may be as high as 70% in immunocompromised individuals.

Tables

Contributor Information and Disclosures

Author

Sandra G Gompf, MD, FACP, FIDSA Associate Professor of Infectious Diseases and International Medicine, University of South Florida College of Medicine; Chief, Infectious Diseases Section, Director, Occupational Health and Infection Control Programs, James A Haley Veterans Hospital